1. Field of the Invention This invention relates to novel C.sub.5 -trans-substituted haloalkyl mevalonolactones and desmethyl homologues thereof. This invention also relates to a novel method for preparing 5-trans-substituted mevalonolactones which are useful as intermediates in the synthesis of biologically active derivatives evidencing, e.g., hypocholesteremic activities. This invention in addition relates to a method for preparing such hypocholesteremic derivatives.
2. Description of the Background
Many synthetic routes for preparing mevalonolactone derivatives have been developed, most of them yielding stereoisomeric mixtures of the 3,5-dyhydroxy moiety of the mevalonolactone system.
The two stereo isomers are referred to as either cis/trans or threo/erythro depending upon whether the compounds are in the lactone (cyclic) or open chain form which are depicted in Scheme III hereinbelow.
Only one of the isomers in these mixtures usually shows significant biological activity. This is generally the trans lactone isomer which corresponds to the erythro isomer of the open chain system. The general synthetic methods known for the preparation of gamma and delta butyrolactones produce mixtures of the two stereoisomers. Non chiral mixtures of gamma or delta aliphatic lactones have been prepared by a variety of methods (see, U.S. Pat. Nos. 2,420,250; 3,992,417; 4,175,089; 2,569,064; 2,968,568; 4,309,352; 3,346,594; 4,499,289; 4,348,535; 4,513,005 and 4,622,338, among others)
Newer synthetic schemes to obtain derivatized lactones other than the six-member ring lactone disclosed herein seem to favor the trans isomer over the cis isomer However, none of the known processes results in a trans isomer substantially free of the cis isomer (see, Gonzalez and Bartlett, "Stereocontrolled Iodolactonization of Acyclic Olefinic Acids: The trans and cis isomers of 4,5-dihydro-5-iodomethyl-4-phenyl-2(3H)-furanone", Organic Synthesis 64: 175 (1985); A. Bongini, G. Cardillo, M. Orena, G. Porzi, and S Sandri, "Regio- and Stereo-controlled Synthesis of Epoxy Alcohols and Triols from Allylic and Homoallylic Alcohols via Iodo Carbonates", J. Org. Chem 1982, 47, 4626-4633; Wang et al, J. Amer. Chem Soc 103:6538 (1981); Hirama et al, Ibid 104: 4251 (1982); Grieco et al, Ibid. 105:1403 (1983); Girotra et al, Tetrahedron Lett. 23:5501 (1982); Girotra et al, Ibid. 24:3687 (1983); Hirama et al, Tetrahedron Lett 24:1811 (1983); Danishefsky et al, J. Amer Chem. Soc. 104:358 (1982); Funk et al, J. Org. Chem. 47:180 (1982); Deutsch et al, Ibid. 47:2682 (1982); Prugh et al, Tetrahedron Lett. 23:281 (1982); Wang et al, Ibid. 23:4305 (1982); Heathcock et al, Ibid. 23:4747 (1982); Lee et al, J. Org. Chem 47:4750 (1982); Anderson et al, Tetrahedron Lett. 24:1373 (1983); Kuo et al, J. Org. Chem 48:1991 (1983); Deutsch et al, Tetrahedron Lett 24:3701 (1983); Funk et al, Ibid 25:1655 (1984); Majeweski et al, Ibid. 25:2101 (1984); Prasad et al, Ibid. 25:2435 (1984); Rosen et al, J. Org. Chem. 49:3994 (1984); Wang et al, J. Amer. Chem Soc. 106 3811 (1984); Falck et al, Tetrahedron Lett 25:3563 (1984); and Funk et al, J. Amer Chem. Soc. (1985), U.S. Pat. No. 4,503,072 to Hoffman et al; U.S. Pat. No. 4,582,915 to Sleteinger et al and U.S. Pat. No. 4,342,767 to Albers-Schonberg et al, among others). Some of these methods are totally synthetic while others rely on an initial fermentation procedure utilizing microorganisms which produces a biologically active isomer in combination with synthetic steps which permit the modification of the thus obtained compound However, no purely synthetic method is known which yields a 3,5-trans 6-substituted mevalonolactone which is substantially free of the cis isomer.
Accordingly, there is still a need for a stereospecific method for the synthesis of 5-transubstituted haloalkyl mevalonolactones and derivatives thereof which is simple to practice, proceeds with high yield and results in the trans isomer substantially in the absence of the cis isomer. There is also a need for haloalkyl mevalonolactones and desmethyl derivatives thereof which are useful as intermediates for the preparation of the biologically active derivatives thereof.